The present invention is directed to a dual phase carrier system for pharmaceutically active compounds and also to compssitions useful for the treatment of dermatomycoses fungal infections. In a specific embodiment, the invention is directed to a composition containing griseofulvin which is topically applied to dermatophytic infections.
In many applications, it is desirable to topically apply pharmaceutically active compounds. One particular application is the treatment of dermatophytic infections. A dermatophytic infection is caused by the invasion of fungi into the keratinized layers of the epidermis, hair and nails of human beings and other animals. There are numerous fungi, such as T. rubrum, Microsporum Canis, T. interdigitale, and other known fungi that can cause these types of infections. The treatment of these infections typically involves administering one or more known types of antifungal agents, e.g. griseofulvin, clotrimazole, miconazole nitrate and thiapendazole, either orally or topically depending on the particular anti-fungal agent used. While certain antifungal agents may be applied topically or orally, certain antifungal agents, e.g. griseofulvin, have generally only been administered orally. Typically, griseofulvin may be administered when the dermatophytic infection has not been successfully treated with the topical application of other antifungal agents.
Despite the effectiveness of orally administered griseofulvin there is concern that the oral use of griseofulvin includes a risk of toxicity and carcinogenesis. It is generally believed that these risks may be reduced if griseofulvin could be successfully topically administered. The topical administration of griseofulvin has been hindered by the lack of a suitable carrier, since griseofulvin can not be topically applied and absorbed through the dermis in its natural solid or powder state. Furthermore, griseofulvin is insoluble in water and only slightly soluble in common solvents, such as dimethylsulfoxide, dimethylformamide and acetone which are typically used as pharmaceutical carriers. The following articles generally discuss the topical application of griseofulvin using various carrier systems.
"Topical griseofulvin therapy of that which is called tinea pedis", by Goldman et al, ASMC DermatoVenereologica, line 39, page 454-460 (1959);
"The activity of various topical griseofulvin preparations and the appearance of oral griseofulvin in the stratum corneum", by Knight, British Journal of Dermatology, Vol. 91, pages 49-55 (1974);
"Topically applied griseofulvin in the treatment of superficial dermatomycoses in Egypt", by H. Abgel-Aal et al, Journal International Medical Research, Vol. 5, pages 382-286 (1977);
"Topically applied griseofulvin in prevention and treatment of Trichophyton mentagrophytes" by Epstein et al, Archives of Dermatology, Vol. 111, pages 1293-1296 (October 1975);
"Evaluation of the effectiveness of griseofulvin, tolnaftate, and placebo in the topical therapy of superficial dermatophytoses" by Zarowny et al, The Journal of Investigative Dermatology, Vol. 64 pages 268-272 (1975);
"Topical treatment of experimental ringworm in guinea pigs with griseiofulvin in dimethylfoxide" by Post and Saunders, Canadian Veterinary Journal, Vol. 20, pages 45-48 (February 1979);
"Topically applied antifungal agents" by Wallace et al, Archives of Dermatology, Vol. 113, pages 1539-1542 (November 1977).
The carrier systems discussed by these articles may be generally classified as consisting of highly volatile solvents, oily solvents or ointments. Some of these carrier systems were found to be ineffective, or if at least partially effective, exhibited other drawbacks. Generally, the highly volatile solvents, e.g. alcohol, dissipated before sufficient time had elapsed for the griseofulvin to be absorbed through the dermis, leaving a residue of griseofulvin powder on the dermis surface. The oily solvents or ointment carriers, even when demonstrated as a potentially effective as a carrier, typically was applied in relatively excessive amounts leaving an oily residue on the dermis even after the lapse of an extended period of time. Furthermore, some of the carrier solvents found effective, i.e. trichloroethanol and dimethylsulfoxide, caused irritation to the dermis when used over extended periods of time.
Topical griseofulvin compositions are also disclosed in U.S. Pat. No. 3,899,578, issued to Bird et al, Aug. 12, 1975. The disclosed compositions are comprised of griseofulvin dissolved in various high boiling, volatile solvents, e.g. propylene carbonate, dimethylphthalate, 3-phenoxypropanol, 4-chlorophenoxyethanol, phenoxyethanol, phenylethanol, eugenol and benzyl alcohol. Benzyl alcohol in combination with dimethyl phthalate, propylene carbonate or eugenol are disclosed as preferred solvent carriers. The useful compositon may be diluted with ethanol, n-propanol, isopropanol, propylene glycol or glycerol. However, the disclosed compositions would be generally classified as a gel, ointment or paste due to the large amount of the low volatile solvent used in their preparation. Thus, these compositions will leave an oily residue for a considerable amount of time after application. This potentially delays or hinders the absorption of griseofulvin since it is believed that griseofulvin preferably remain solubilized in the oily layer of the composition.
There thus remains a need for a topically applied solvent carrier system which does not cause irritation or leave an substantially large oily residue, which potentially delays or hinders absorption of the pharmaceutically active compound being applied, and particularly a carrier system for the topical application of griseofulvin.